title: FANCD2 activates transcription of TAp63 and suppresses tumorigenesis.
abstract: Fanconi anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras-oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population.
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Eunmi
authors.initials: E
authors.lastname: Park
authors.forename: Hyungjin
authors.initials: H
authors.lastname: Kim
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Kim
authors.forename: Benjamin
authors.initials: B
authors.lastname: Primack
authors.forename: Sofia
authors.initials: S
authors.lastname: Vidal-Cardenas
authors.forename: Ye
authors.initials: Y
authors.lastname: Xu
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Price
authors.forename: Alea A
authors.initials: AA
authors.lastname: Mills
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
mesh_terms: D000818:Animals; D029681:Arabidopsis Proteins; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D016922:Cellular Senescence; D004249:DNA Damage; D060467:Disease Resistance / Q000235:genetics; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000502:physiology*; D005260:Female; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018307:Neoplasms, Squamous Cell / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination
chemical_list: D029681:Arabidopsis Proteins; C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D010450:Endopeptidases; C579228:USP1 protein, human; D064570:Ubiquitin-Specific Proteases; C579227:Usp1 protein, mouse